This application addresses broad Challenge Area (13): Smart Biomaterials - Theranostics, and specific Challenge Topic, 13-NS-101: Developing novel biomaterials to interfaces with neural activity. Implantable neural interface devices are a critical component to a broad class of emerging neuroprosthetic and neurostimulation systems, in both research and clinical settings. In almost all cases, the performance of the system hinges to a large degree on the performance of the device to record and/or stimulate within quality, stability, and longevity requirements. Recording quality, longevity and stability is highly variable according to numerous reports, and the reactive tissue response that occurs to devices following implantation is a likely key contributing factor. The fundamental challenge is to develop advanced materials and implantable structures that will enable neural interface devices to be implanted in target areas of the brain and remain functional for as long as needed, sometimes stretching into years and decades. This proposal provides an innovative strategy that uses leading-edge biocompatible polymers to develop innovative 'microthread neural probes'that are ultra-small and flexible, with bioactive surfaces and nanostructured electrode sites for enhanced signal transduction. We will create these microthread probes using advanced carbon nanotube (CNT) and bioactive polymer coating technologies. We will focus on the problem of chronic neural recording of spike activity because this is considered to be the most sensitive assay of neural interface material performance. Aim 1 is to develop base versions of microthread neural probes for chronic neural recording. This aim will establish a technology foundation and set of validation benchmarks for microthread neural probes. The primary tasks will be to integrate CNT and functionalized polymer coating technologies into microthread neural probes that can be reliably inserted into the brain and used for chronic recording. The design space includes size, flexibility, strength, conductivity, site electrical characteristics, insulating coating, insertion techniques, and electrode size. Aim 2 will develop functionalized microthread neural probes for targeted intervention in chronic tissue responses. The guiding hypothesis is that immobilized biomolecules on the microthread probe surface be effective for intervening with specific reactive tissue responses, including biofouling, inflammation, and neurotoxicity. This proposal is innovative in its biologically inspired strategies and use of leading-edge biomaterials to develop chronic neural probes that are small (sub-cellular), flexible, and strong with excellent electrical and transduction properties, and have sophisticated surfaces tailored for specific biological processes. This project is likely to make significant contributions through developing advanced neural probes for long-term (permanent), high quality and selective neural recording. The outcomes of this project are also likely to establish new biologically inspired paradigms for creating long-lasting, high-fidelity neural interfaces with biomimetic materials. This project will impact both the neuroscience research community, and clinical communities (neurosurgeons, neurologists, and patients) that use and benefit from neuroprosthetic- and neurostimulation-based treatments interventions. The public health relevance of this project is to improve neural prosthetic and neural stimulation devices for treatment of neurological diseases or injury.